JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

Transcription

1 This is an author produced version of an article that appears in: JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM The internet address for this paper is: Published text: G Minniti, D Traish, S Ashley, A Gonsalves, M Brada (2005) Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: Update after an additional 10 years, Journal of Clinical Endocrinology and Metabolism, Vol. 90(2), Institute of Cancer Research Repository Please direct all s to: publications@icr.ac.uk

2 Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma: update after further 10 years Minniti G 1, Traish D 1, Ashley S 2, Gonsalves A 1, Brada M 1 Neuro-oncology Unit 1, Computing Department 2, The Institute of Cancer Research and the Royal Marsden NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK, and Fulham Road, London SW3 6JJ Corresponding author: Prof. Michael Brada The Institute of Cancer Research and The Royal Marsden NHS Trust Downs Road, Sutton, Surrey SM2 5PT, UK tel: 44 (0) (academic) fax: 44 (0) michael.brada@icr.ac.uk

3 Abstract Background. We assessed the risk of second brain tumours in a cohort of patients with pituitary adenoma treated with conservative surgery and external beam radiotherapy. Methods. 426 patients (UK resident) with pituitary adenomas received radiotherapy at the Royal Marsden Hospital (RMH) between 1962 and They were followed up for 5647 person-years. The cumulative incidence of second intracranial tumours and systemic malignancy was compared with population incidence rates through the Thames Cancer Registry and through National Health Service Central Register (NHSCR, previously OPCS) to record death and the potential causes. Findings: Eleven patients developed a second brain tumour, including 5 meningiomas, 4 high grade astrocytomas, one meningeal sarcoma and one PNET. The cumulative risk of second brain tumours was 2.0% (95% CI: %) at 10 years and 2.4% (95% CI: %) at 20 years measured from the date of radiotherapy. The relative risk (RR) of second brain tumour compared with the incidence in the normal population was 10.5 (95% CI: ). The RR was 7.0 for neuro-epithelial and 24.3 for meningeal tumours. The RR was 24.2 (95% CI ), 2.9 (95% CI 0-8.5) and 28.6 (95% CI ) during the interval 5-9, 10-19, and > 20 years after radiotherapy (4 cases occurred >20 years after treatment). There was no evidence of excess risk of second systemic malignancy. Conclusions: An additional 10 years update confirms our previous report of an increased risk of second brain tumours in patients with pituitary adenoma treated with surgery and radiotherapy. The 2.4% risk at 20 years remains low. and should not preclude the use of radiotherapy as an effective treatment option. However an increased risk of second brain tumours continues beyond 20 and 30 years after treatment. 2

4 Introduction Conventional external beam radiotherapy is effective in achieving control of tumour growth and hormonal hypersecretion in patients with pituitary adenoma. Despite its effectiveness there is concern about late effects of radiation with second radiation induced brain tumour a particularly feared complication. It is recognised that radiation is associated with the development of intracranial tumours following therapeutic cranial irradiation for acute lymphoblastic leukaemia (1), tinea capitis (2) (3), and intracranial tumours (4) (5) (6). Increased risk of second brain tumours has also been demonstrated in animals exposed to radiation (7). We previously reported an actuarial cumulative risk of developing a second brain tumour in patients with pituitary adenoma treated with surgery and radiotherapy as 1.0% at 10 years and 1.9% at 20 years after treatment with a relative risk compared to normal population of 10.5 (8). The results were confirmed by some investigators (9) although other series reported lower incidence (10) (11). While there is a debate about the relative and actuarial risk of developing a second brain tumour it must be acknowledged that the relationship between radiotherapy and second brain tumour remains putative with no clear demonstration of one treatment factor as the only cause. The reason for singling out radiation as the most likely culprit is the evidence for radiotherapy as the main determinant in other conditions and the relative lack of evidence of association between pituitary adenoma and second malignancy. Regardless of the debate on causation we continued detailed follow up of the cohort of patients with pituitary adenoma reported previously. In this report we set out to assess the potential change in the actuarial incidence and relative risk of second tumour with additional 10 years of follow-up in an enlarged cohort containing the previously reported series. 3

5 Patients and methods Four hundred and twenty-six patients (247 males and 179 females) with pituitary adenomas resident in the UK, received radiotherapy at the Royal Marsden Hospital (RMH) between 1962 and Part of the present series includes the previous cohort of 334 patients published in 1992 (8). The remaining 92 patients were treated in our institution between 1987 and The patient and treatment characteristics are shown in Table 1. On the basis of clinical characteristics and endocrinological assessment 263 patients had non-functioning adenoma and 135 had a secreting pituitary adenoma. In 28 patients the secretory status was not known. Three hundred and forty-one patients had surgery prior to radiotherapy and 72 patients had no prior surgery. The diagnosis of adenoma was confirmed histologically in 334 patients and in 92 the diagnosis was based on endocrinological and/or radiological features. 75% of patients received radiotherapy to a dose of Gy in fractions using a conventional three-fields technique (usually 45Gy in 25 fractions). A total dose 50 Gy was delivered to 23% of patients. Patients were treated in a supine position in an immobilization device with two wedged lateral fields and one anterior oblique field delivered to a target volume encompassing the pituitary tumour and a 1-2 cm margin. After treatment the majority of patients were followed up at RMH or in an Endocrine clinic in adjacent hospitals. Patients not seen for more than one year from the date of analysis were followed up through a postal questionnaire sent to the initial referring hospital and/or general practitioner. The cohort was also flagged for second tumours through the Thames Cancer Registry and through National Health Service Central Register (NHSCR, previously OPCS) to record death and the potential causes. The median follow-up for the entire series was 12 years ranging from 0 to 38.4 years; 126 patients were followed up more than 20 years. The total follow-up consisted of 5,647 person years. 4

6 Statistical considerations The risk to patients of a second brain tumour was estimated by the Kaplan- Meier survival method (12) and the time of the event was measured from the beginning of radiotherapy. Predictors of risk of second tumour were analysed in a univariate analysis by the log-rank test (13). The second tumour data were compared to the expected numbers of tumours in the general population using national age and sex specific incidence rates (Office for National Statistics, England and Wales 1992). All p-values were 2 sided and based on the Poisson distribution (14). Results Incidence of second tumours Eleven of the 426 patients developed a second intracranial tumour after surgery and radiotherapy for pituitary adenoma (Table 2). Five patients had a meningioma, four a high grade astrocytoma, one a meningeal sarcoma, and one a PNET. The diagnosis was confirmed histologically in all but one, in whom the presence of a meningioma was diagnosed by CT imaging. In all cases tumours were identified within the region of entry of radiation fields, and in one case in the pituitary fossa. Tumours were diagnosed 6 to 34 years after radiotherapy with a mean (and SD) of 6.7 ± 1.7 years for astrocytoma and 20.8 ± 10.0 years for meningeal tumours, respectively. Age, sex, pituitary adenoma type, radiation dose, tumour extent, and medical treatment were found not to be predictive of development of second tumours on univariate analysis. Thirty-seven patients developed a second tumour at peripheral sites during the follow-up (Table 3). 5

7 Comparison of risk of second tumour to general population The cumulative risk of second brain tumours was 2.0% (95% CI: %) at 10 years, 2.4% years (95% CI: %) at 20 years, and 8.5% (95%CI %) at 30 years measured from the date of radiotherapy (Figure 1). Compared to an age and sex matched normal population, this represented an increased risk of brain tumours (relative risk 10.5; 95% CI ). The relative risk of developing a brain tumour was 7.0 for glial and 24.3 for meningeal tumours (Table 4). After stratification for interval between treatment and presence of second tumour, the relative risk was 24.2 over the first 10 years and 23.2 at 30 years, respectively, with an apparently low relative risk between 10 and 19 years, reflecting the different timing of development of glial and meningeal tumours (Table 5). No evidence of excess risk of second systemic malignancy was observed compared to the expected risk in the general population. Discussion We demonstrated an increased risk of second brain tumours in patients with pituitary adenoma treated with surgery and external beam radiotherapy. Second tumours diagnosed were meningiomas and malignant neuroepithelial tumours, particularly high grade astrocytomas. The actuarial cumulative incidence of second brain tumours was 2.4% at 20 years, with a relative risk of 10.5 compared to the general population. The study largely confirms the results reported previously in a smaller cohort of 334 patients and shorter follow-up (8). The present data report a larger number of patients with further cases of second brain tumour and additional 10 years of follow-up and therefore provide a greater confidence in the results. It is therefore of interest that the magnitude of risk of developing a second brain tumour remains unchanged. The new and perhaps not unexpected finding is the occurrence of second tumours more than 20 and 30 6

8 years after treatment with a broadly similar relative risk in the later period. The results are in keeping with the reported cumulative risk of secondary glioma after radiation of 2.7% at 15 years in a cohort of 305 patients with pituitary adenomas, and a relative risk of malignant brain tumour of 16 (15). However, other studies reported only a moderate or no increased risk of second brain tumours after irradiation of pituitary adenomas (16) (11) (17). In a more recent study Erfurth et al (18) reported a cohort of 325 patients irradiated with a median dose of 40 Gy (< 2 Gy per fraction) with three cases of intracranial tumour (2 astrocytomas and one meningioma) with a relative risk of second brain tumour of 2.7 compared to the normal population. As the latency period for development of meningiomas is decades after radiotherapy (19), the different length of follow-up in the reported studies may in part account for the apparent discrepancy. The lower dose used may also be associated with a lower risk. In addition, meningiomas may be asymptomatic and the lower incidence in some studies (17) (11) (10) could be an underestimate if patients were lost to follow up and cause of death not reported. The results reported here may also overestimate the risk. Pituitary adenoma population is under close scrutiny with frequent recourse to imaging and asymptomatic benign meningiomas are more likely to be noted than in the normal population. Although the actuarial risk is not disputed, the denominator in the calculation of relative risk may underrepresent the real situation and therefore the true relative risk may be somewhat lower. It is generally assumed that ionising radiation is responsible for inducing second tumours in the brain (3) and it remains the only recognised environmental causative factor in the development of meningioma (20) (19) (21) (22) occurring after high and low dose radiation. The relative risk of developing meningioma in patients irradiated in childhood for tinea capitis has been reported as 9.5 after a mean dose of 1.4Gy (3). The relative risk of developing of a glioma after prophylactic cranial irradiation 7

9 for leukaemia is reported as (1). This corresponds to a year cumulative risk of % amongst survivors of childhood acute lymphoblastic leukaemia. Higher incidence of 12.8% has also been reported (23). Individual case reports, have suggested an increased risk of a second brain tumour after irradiation of other primary brain tumours (24) (24) (6) (25) (17) (24) (5) (26). However, the relative risk is not reported as there is no information on the size of the denominator (cohort of patients studied). There is debate about the incidence of second brain tumours in patients with pituitary adenoma treated with surgery alone. While there are recognised inherited syndromes associated with increased risk of developing brain tumours such link has not been described for patients with pituitary tumours. However, individual cases of brain tumours, especially meningioma have been reported in previously untreated pituitary adenoma patients (17) (27). Overall, there is no clear evidence of increased incidence of brain tumours, regardless of the type of adenoma (10). The only apparent association between malignant disease and pituitary adenoma is the slightly elevated risk of colon cancer in patients with acromegaly (28). Our conclusion remains that while the role of irradiation remains unproven, radiation is likely to be a contributing factor in the development of second brain tumours in patients with pituitary adenoma treated with conservative surgery and radiotherapy. New techniques of radiotherapy such as radiosurgery and fractionated stereotactic radiotherapy, which reduce the volume of normal brain receiving high radiation doses (for details see (29) (30), have been considered to lead to reduction in the incidence of second tumours. Although no cases of second tumour after fractionated stereotactic radiotherapy or radiosurgery for pituitary adenomas have so far been reported, the occurrence of gliomas has been described after radiosurgery for meningioma (31) or other brain tumours (32) (33). On theoretical grounds there is no reason to believe that radiation in whichever form will not be a future causative factor. The present lack of cases may simply be a reflection of the small number of patients treated and lack of adequate long term follow up. Radiosurgery or stereotactic radiotherapy, which aim for more localised high dose irradiation, frequently irradiate larger 8

10 volumes of normal brain to low doses and may increase the risk of second tumours. Intensity modulated radiotherapy (IMRT), which is a sophisticated technique of localised conformal radiotherapy has, in fact, been predicted to increase the risk of radiation induced second tumours (34). To demonstrate a change in the incidence of second brain tumours will require large cohorts of patients with follow up in excess of 10 and 20 years and such data is currently not available. As reported previously, astrocytomas occur earlier than meningiomas with a median time of 6.7 ± 1.7 years and 20.8 ±10.0 years respectively and this is in keeping with other studies (19) (4). A new finding is the occurrence of meningioma 30 years after treatment which suggests a continued need for surveillance. Meningiomas have been reported to occur up to 50 years after irradiation with a median time in the region of 19.5 years based on reported cases (19). One patient developed a PNET 5 years after radiotherapy. The development of a PNET following prophylactic craniospinal irradiation has been reported (19) and a recent publication suggests that it may be more common than suggested previously (35). In summary, the study confirms the previous report of an increased risk of second brain tumours in patients with pituitary adenoma after surgery and radiotherapy. While unproven, the circumstantial evidence points to the role of ionising radiation in the development of second brain tumours. However, a potential genetic link between pituitary tumours and gliomas and meningiomas cannot be excluded. Despite more cases noted with longer follow up, the relative risk remains unchanged and the actuarial incidence with 2.4% risk at 20 years remains low. The contribution of second brain tumours to long term mortality is minimal with predominant risk of mortality from cerebrovascular events (36) (37) (38) so far of complex multifactorial aetiology. The low incidence of second brain tumours should therefore not preclude the use of radiotherapy as an effective treatment modality in patients with otherwise uncontrolled pituitary adenomas. 9

11 Acknowledgment This work was supported in part by the Neuro-Oncology Research fund, The Royal Marsden NHS Trust and Cancer Research UK. The work was undertaken by the Royal Marsden NHS Trust who received a proportion of its funding from the NHS Executive; the views expressed are those of the authors and not necessarily those of the NHS Executive. 10

12 Table 1. Characteristics of patients with pituitary adenoma Patients with pituitary adenoma Total in series 426 Age : Median (Range) 50 (15-78) Sex : Male : Female 247 : 179 Primary referral 382 Referral at recurrence 44 Tumour type Hormone secreting 135 Non-secreting 263 Unknown 28 Radiation dose < > Technique of radiotherapy 2 field 3 3 field 410 Rotation 10 Not known 3 Extent of surgery Complete 9 Incomplete 332 Biopsy / No surgery 72 Not known 13 Years of follow-up

13 Table 2 Characteristics of 11 patients with second brain tumours Patient Age (RT) Sex type of years second tumour Site adenoma since RT 1 22 m nonfunctioning 34 meningioma unknown 2 19 f GH-secreting 10 meningioma Right sphenoid ridge 3 54 m nonfunctioning 6 astrocytoma Left frontal 4 22 f unknown 22 meningioma unknown 5 48 f nonfunctioning 7 meningeal sarcoma Sella 7 39 f nonfunctioning 29 meningioma unknown 8 58 f unknown 21 meningioma Right temporal 9 40 f nonfunctioning 9 astrocytoma Right temporal m GH-secreting 6 astrocytoma unknown m nonfunctioning 6 PNET Right frontal region

14 Table 3. Incidence and relative risk of second extracranial tumours in 426 patients with pituitary adenomas. Second tumour observed expected Relative risk 95% CI p value Lip, oral cavity & pharynx ( ) Stomach (151) Colon and rectum ( ) Other digestive organs (150,152, ) Respiratory & intrathoracic organs ( ) Female Breast (174) Female genitourinay organs ( ) Male genitourinay organs ( ) Lymphatic & haematopoietoc tissue ( ) Other & unspecified sites ( ,175, , ) TOTAL

15 Table 4. Incidence and relative risk of second brain tumours in 426 patients with pituitary adenomas. Second tumour observed expected Relative risk 95% CI p value Benign brain tumours (Meningioma) Malignant brain tumours (Glioma / PNET) All brain tumours

16 Table 5. Timing of Incidence and relative risk of second brain tumours in 426 patients with pituitary adenomas. Years since No of observed expected Relative risk 95% CI p value radiotherapy patients Total

17 Figure 1. Cumulative actuarial probability of developing a second brain tumour. Error bars repersent 95% confidence intervals % Incidence Years Since Radiotherapy 16

18 References: 1. Neglia JP, Meadows AT, Robison LL Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med 325: Sadetzki S, Flint-Richter P, Ben-Tal T, Nass D 2002 Radiationinduced meningioma: a descriptive study of 253 cases. J Neurosurg 97: Ron E, Modan B, Boice JD, Jr Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 319: Kaschten B, Flandroy P, Reznik M, Hainaut H, Stevenaert A 1995 Radiation-induced gliosarcoma. Case report and review of the literature. J Neurosurg 83: Liwnicz BH, Berger TS, Liwnicz RG, Aron BS 1985 Radiationassociated gliomas: a report of four cases and analysis of postradiation tumors of the central nervous system. Neurosurgery 17: Simmons NE, Laws ER, Jr Glioma occurrence after sellar irradiation: case report and review. Neurosurgery 42: Lonser RR, Walbridge S, Vortmeyer AO Induction of glioblastoma multiforme in nonhuman primates after therapeutic doses of fractionated whole-brain radiation therapy. J Neurosurg 97: Brada M, Ford D, Ashley S Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. Br Med J 304: Tsang RW, Brierley JD, Panzarella T, Gospodarowicz MK, Sutcliffe SB, Simpson WJ 1994 Radiation therapy for pituitary adenoma: treatment outcome and prognostic factors. Int J Radiat Oncol Biol Phys 30: Erfurth EM, Bulow B, Mikoczy Z, Hagmar L 2001 Incidence of a second tumor in hypopituitary patients operated for pituitary tumors. J Clin Endocrinol Metab 86: Bliss P, Kerr GR, Gregor A 1994 Incidence of second brain tumours after pituitary irradiation in Edinburgh Clin Oncol R Coll Radiol 6: Kaplan EL, Meier P 1958 Non parametric estimation from incomplete observations. J Am Stat Assoc 53: Peto R, Pike MC, Armitage P Design and analysis of randomised clinical trials requiring prolonged observation of each patient. Part 2 analysis and examples. Br J Cancer 35:1-39

19 14. Breslow NE, Day NE 1987 The design and analysis of cohort studies. In. IARC Publishers, Lyon, p Tsang R, Laperriere N, Simpson W, Brierley J, Panzarella T, Smyth H 1993 Glioma arising after radiation therapy for pituitary adenoma: a report of four patients and estimation of risk. Cancer 72: Erfurth EM, Bengtsson BA, Christiansen JS, Bulow B, Hagmar L 2001 Premature mortality and hypopituitarism. Lancet 357:1972; discussion Jones A 1991 Radiation oncogenesis in relation to the treatment of pituitary tumours. Clinical Endocrinology 35: Erfurth EM, Bulow B, Mikoczy Z, Svahn-Tapper G, Hagmar L 2001 Is there an increase in second brain tumours after surgery and irradiation for a pituitary tumour? Clin Endocrinol (Oxf) 55: Harrison MJ, Wolfe DE, Lau TS, Mitnick RJ, Sachdev VP 1991 Radiation-induced meningiomas: experience at the Mount Sinai Hospital and review of the literature. J Neurosurg 75: Bondy ML, Wrensch MR 1996 Epidemiology of primary malignant brain tumours. In: Yung WKA (ed) Cerebral Gliomas. Bailliere Tindall, London, pp Longstreth WT, Jr., Dennis LK, McGuire VM, Drangsholt MT, Koepsell TD 1993 Epidemiology of intracranial meningioma. Cancer 72: Rubinstein AB, Shalit MN, Cohen ML, Zandbank U, Reichenthal E 1984 Radiation-induced cerebral meningioma: a recognizable entity. J Neurosurg 61: Relling MV, Rubnitz JE, Rivera GK High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet 354: Salvati M, Frati A, Russo N Radiation-induced gliomas: report of 10 cases and review of the literature. Surg Neurol 60:60-7; discussion Cavin LW, Dalrymple GV, McGuire EL, Maners AW, Broadwater JR 1990 CNS tumor induction by radiotherapy: a report of four new cases and estimate of dose required. Int J Radiat Oncol Biol Phys 18: Kitanaka C, Shitara N, Nakagomi T Postradiation astrocytoma. Report of two cases. J Neurosurg 70: Abs R, Parizel PM, Willems PJ The association of meningioma and pituitary adenoma: report of seven cases and review of the literature. Eur Neurol 33:

20 28. Orme SM, McNally RJ, Cartwright RA, Belchetz PE 1998 Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab 83: Brada M, Ajithkumar T, Minniti G In press Radiosurgery for pituitary adenomas; a review. Clin Endocrinol 30. Ajithkumar TV, M B 2004 Stereotactic linear accelerator radiotherapy for pituitary tumours. Treatments in Endocrinology 3: Yu JS, Yong WH, Wilson D, Black KL 2000 Glioblastoma induction after radiosurgery for meningioma. Lancet 356: Shamisa A, Bance M, Nag S Glioblastoma multiforme occurring in a patient treated with gamma knife surgery. Case report and review of the literature. J Neurosurg 94: Kaido T, Hoshida T, Uranishi R Radiosurgery-induced brain tumor. Case report. J Neurosurg 95: Hall EJ, Wuu CS 2003 Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 56: Hader WJ, Drovini-Zis K, Maguire JA 2003 Primitive neuroectodermal tumors in the central nervous system following cranial irradiation: a report of four cases. Cancer 97: Brada M, Burchell L, Ashley S, Traish D 1999 The incidence of cerebrovascular accidents in patients with pituitary adenoma. Int J Radiat Oncol Biol Phys 45: Brada M, Ashley S, Ford D, Traish D, Burchell L, Rajan B 2002 Cerebrovascular mortality in patients with pituitary adenoma. Clin Endocrinol (Oxf) 57: Tomlinson JW, Holden N, Hills RK Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 357: